"Toxoplasma gondii: neuro-intestinal interactions"

描述（由申请人提供）：在免疫反应过程中，大脑和免疫系统之间存在双向通信以维持体内平衡。两个主要的通路系统参与这种交叉交流，下丘脑-垂体-肾上腺（HPA）轴和交感神经-肾上腺-髓质（SAM）系统。SAM系统的激活导致从交感神经末梢和肾上腺髓质释放儿茶酚胺。糖皮质激素和儿茶酚胺都会影响免疫反应并加剧艾滋病毒疾病。有趣的是，并非所有慢性弓形虫感染的艾滋病患者都会发展为临床疾病，这表明除了CD4 T细胞计数低外，还有其他因素影响发病机制。我们的长期目标是了解应激激素和神经肽如何调节机会性寄生虫弓形虫的感染。本应用程序的目的是研究去甲肾上腺素（N-EPI）在应激条件下口服感染小鼠肠道病理中的作用，去甲肾上腺素是SAM系统的主要介质，作为辅助因子。这项研究的基本原理是，易感的C57BI/6小鼠在经口感染弓形虫后死亡，部分原因是由干扰素(IFN)-？由原膜（LP） CD4+ T细胞释放；而冷水应激（CWS）可能通过降低CD4+ T细胞驱动的肠道病理来提高这些小鼠的存活率。我们假设一个潜在的机制可能涉及应激动物肠道T细胞活性的肾上腺交感调节，导致肠道对弓形虫感染的免疫反应改变。为了实现这一应用的目标，我们将采用轻度物理应激源（CWS）和低毒力的弓形虫菌株（ME49菌株）。研究的两个具体目标是：(1)在体外确定交感神经系统（SNS）的主要介质N-EPI在CWS期间对LP树突状细胞和CD4+ T细胞的作用；(2)确定N-EPI和外周交感神经支配在CWS和感染期间LP细胞反应中的作用。在这项研究完成后，我们期望确定N-EPI在经口弓形虫感染期间肠道细胞反应的应激诱导变化中的贡献。除了在理解由中枢神经系统调节的正常生理和宿主防御过程中具有基本应用外，这些结果将在设计旨在抑制炎症反应增强引起的病理的新治疗策略方面具有重要价值。

DESCRIPTION (provided by applicant): During an immune response bi-directional communication exists between the brain and the immune system to maintain homeostasis. Two major pathway systems are involved in this cross-communication, the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenal-medullary (SAM) system. Activation of the SAM system leads to release of catecholamines from sympathetic nerve terminals and from the adrenal medulla. Both glucocorticoids and catecholamines affect immune responses and exacerbate HIV disease. Interestingly, not all AIDS patients chronically infected with Toxoplasma develop clinical disease suggesting factors in addition to low CD4 T cell counts influence pathogenesis. Our long-range goal is to understand how stress hormones and neuropeptides regulate infection by the opportunistic parasite Toxoplasma gondii. The objective of this application is to investigate the role of the nor-epinephrine (N-EPI), the main mediator of the SAM system as cofactor in the intestinal pathology of mice orally infected under conditions of stress. The rationale behind this research centers in the fact that susceptible C57BI/6 mice died after peroral infection with T. gondii due to intestinal pathology driven in part by interferon (IFN)-? released by lamina propia (LP) CD4+ T cells; while cold water stress (CWS) enhanced the survival of these mice likely by decreasing CD4+ T cell-driven intestinal pathology. We hypothesize that a potential mechanism may involve adreno-sympathetic regulation of intestinal T cells activity in stressed animals, leading to altered intestinal immune responses to T. gondii infection. To accomplish the objectives of this application, we will employ a mild physical stressor (CWS) and a low virulent strain of T. gondii (ME49 strain). Two specific aims will be pursued: (1) to determine ex vivo the contribution of N-EPI, the main mediators of the sympathetic nervous system (SNS) on LP dendritic cells and CD4+ T cells during CWS; and (2) to determine the contribution of N-EPI and peripheral sympathetic innervations on LP cellular responses during CWS and infection. At the completion of this research, we expect to have determined the contributions of N-EPI to the stress-induced changes in intestinal cellular responses during peroral T. gondii infection. In addition to having basic application in understanding normal physiologic and host defensive processes modulated by the central nervous system, these results will be of great value in designing new therapeutic strategies aimed at curbing pathology induced by enhanced inflammatory responses.